Abstract: PO0590
Development of a CKD Model in Cynomolgus Monkeys and Its Application to Test Zampilimab, a Monoclonal Antibody (mAb) Specific for Human Transglutaminase 2 (TG2)
Session Information
- CKD Mechanisms - 1
October 22, 2020 | Location: On-Demand
Abstract Time: 10:00 AM - 12:00 PM
Category: CKD (Non-Dialysis)
- 2103 CKD (Non-Dialysis): Mechanisms
Authors
- Huang, Linghong, UCB Pharma, Slough, United Kingdom
- Song, James Zhizhan, Prisys Biotechnology, Shanghai, China
- Johnson, Timothy Scott, UCB Pharma, Slough, United Kingdom
Background
TG2, a crosslinking enzyme involved in wound healing, is linked to the development of renal fibrosis. TG2 irreversibly crosslinks proteins via ε(γ-glutamyl) lysine dipeptide bonds, including extracellular matrix (ECM) proteins. TG2 accelerates ECM deposition and renders the matrix resistant to ECM proteases, forcing ECM homeostasis towards accumulation. TG2 also crosslinks large latent TGFβ1 into the ECM, releasing the active pro-fibrotic TGFβ1 dimer.
Zampilimab (IC50 0.2nM, Kd 120pm), a humanized mAb specific for human TG2, is under investigation for the treatment of fibrosis. Application of zampilimab in a primary human cell model of renal fibrosis had positive results; however due to human specificity, zampilimab efficacy cannot be tested in rodent in vivo models.
Methods
A unilateral ureteric obstruction model of CKD was developed in aged cynomolgus monkeys. Zampilimab was applied prophylactically immediately following model induction. TG2 activity was measured using an in-situ activity assay, and zampilimab target occupancy determined by competitive immunofluorescence. Renal fibrosis was measured by computerized image analysis and histopathological scoring of Masson’s trichrome, Picosirius red and H&E stained slides with hydroxyproline measured by amino acid analysis.
Results
Ligation of the left ureter led to development of severe tubulointerstitial fibrosis with elevated TG2 antigen levels and activity, leading to end-stage histology by 6 weeks. This primate model has a greater expansion of the tubular basement membrane than similar rodent models, with histology more closely resembling obstructive disease in man. Following zampilimab intervention in a 4-week study, 7 days post final dose, TG2 activity remained completely inhibited at a high dose, whereas 70% of activity returned at a low dose. However, both zampilimab doses ameliorated the level of renal fibrosis by pathology score, computerized determination of fibrotic index and hydroxyproline.
Conclusion
Our primate model of CKD demonstrated that zampilimab can effectively block TG2 activity and prevent renal fibrosis. A Phase 1/2 study of zampilimab for the treatment of post-renal transplant fibrosis is ongoing (NCT04335578).
Funding
- Commercial Support –